The objectives of this proposal are to define the key metabolic changes which lead to irreversible ischemic heart damage and to determine what related interventions may protect the oxygen-deficient myocardium. The effects of various phases of ischemia, anoxia, and reoxygenation upon a number of metabolic, physiological, and ultrastructural parameters will be investigated. Studies will be made in experimental systems such as the isolated perfused heart, open-chest dog, heart cells, and mitochondrial preparations. The models utilized will provide tests of our working hypothesis, i.e., the tissue long-chain acyl CoA ester (LCACAE)/free carnitine (carn) ratio increases during reversible ischemia or anoxia and may affect the ability of the heart to recover from longer periods of oxygen deficiency. Effects of changes in the tissue LCACAE/carn ratio upon mitochondrial respiration, the adenine nucleotide translocator (ANT), distribution of adenine nucleotides, NADH/NAD and acetyl CoA/CoA ratios, and other key enzyme systems will be examined and correlated with heart functions, e.g., left ventricular contraction; (dp/dt), and cellular or organelle membrane defects. Using such indices of ischemic injury, the ability of carn, acetyl carn (ACcarn), and other agents to protect the ischemic myocardium will be investigated further. Related studies will deal with carn transport systems and the possible regulatory role of carn in cardiac metabolism.